Rationale: Higher rates of sepsis have been reported in minorities. Objective: To explore racial differences in the incidence and associated case fatality of severe sepsis, accounting for clinical, social, healthcare service delivery, and geographic characteristics. Methods: Retrospective population-based cohort study using hospital discharge and US census data for all persons (n= 71,102,655) living in 68 hospital referral regions in 6 states. Measurements: Age-, sex- and race-standardized severe sepsis incidence and inpatient case fatality rates, adjusted incidence rate ratios, and adjusted intensive care unit (ICU) admission and case fatality rate differences. Results: Of 8,938,111 non-federal hospitalizations, 282,292 had severe sepsis. Overall, blacks had the highest age- and sex-standardized population-based incidence (6.08/1000 vs. 4.06/1000 for Hispanics and 3.58/1000 for whites) and ICU case fatality (32.1% vs. 30.4% for Hispanics and 29.3% for whites, p<0.0001). Adjusting for differences in poverty in their region of residence, blacks still had a higher population-based incidence of severe sepsis (adjusted rate ratio (ARR) 1.44 [1.42 to 1.46]) than whites, but Hispanics had a lower incidence (ARR 0.91 [0.90 to 0.92]). Among severe sepsis patients admitted to the ICU, adjustments for clinical characteristics and the treating hospital fully explained blacks' higher ICU case fatality. Conclusions: Higher adjusted black incidence and the lower Hispanic incidence may reflect residual confounding, or it could signal biologic differences in susceptibility. Focused interventions to improve processes and outcomes of care at the hospitals that disproportionately treat blacks could narrow disparities in overall mortality from severe sepsis.